NAS PHARMACOLOGIC MANAGEMENT

William Driscoll, DO (University of Florida/Jacksonville)Doug Hardy, MD (Winnie Palmer)

Lance Wyble, MD (MEDNAX, Inc. - Bay Care)

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Our speakers

William Driscoll, DO Doug Hardy, MDLance Wyble, MD, MPH

Thank you!

Learning objectives1. Discuss pros & cons of the most commonly

used medications in NAS• 1st line: Morphine, Methadone• 2nd line: Phenobarbital, Clonidine

2. Discuss benefits of complying with a standardized guideline

3. Describe individual hospital pharmacologic guidelines

4. Understand how to develop a process map to communicate pharmacologic management

PHARMACOLOGIC MANAGEMENT

1st line: Morphine, Methadone

NAS Therapies in US NICUs

Journal of Perinatology, 34, 867-872

• Morphine & methadone are most commonly used therapies

• Buprenorphine may become more common over time

• New studies support role of clonidine alone in treatment of NAS

MorphineADVANTAGES DISADVANTAGES

• Can be weaned more quickly in general due to its short half life

• Shorter course of treatment

• Shorter hospitalization

• Can be more easily given after discharge if necessary

• Short half life means diligent treatment and scoring during capture and weaning

Methadone• 0.05-0.2 mg/kg every 12-24 hours

ADVANTAGES DISADVANTAGES

• Longer half life means fewer daily doses

• Long half-life may delay weaning• Longer course of

treatment• Longer hospital stay

• Can lead to torsades de pointe in patients with congenital prolonged QT syndrome

Morphine vs. methadone• No good comparisons between morphine

& methadone as primary therapy for NAS• Multiple reviews comparing NAS treatment

with morphine or methadone have found conflicting results regarding length of stay

• Retrospective review of 36 infants treated with morphine or methadone for NAS found higher Cognitive and Gross Motor domains on Bayley-III for those treated with morphine

Takeaways• Maternal methadone dose DOES NOT

foretell likelihood of NAS in infant

• Non-pharmacologic measures are critical to successful treatment

• Centers have been successful with morphine or methadone – get a protocol and STICK TO IT

PHARMACOLOGIC MANAGEMENT

2nd Line: Phenobarbital, Clonidine

Phenobarbital

• 2nd line medication

• Type of drug: Barbiturate

• Pharmacokinetics: Long half life

PhenobarbitalADVANTAGES DISADVANTAGES

• Decreased length of hospital stay (i.e., discharge home on phenobarbital)

• Enteral formulation contains 10% alcohol

• Potential prolonged medication exposure

Surran et. al. Journal of Perinatology 2013

• Data on morphine/clonidine combination vs. morphine/phenobarbital combination

• Phenobarbital combination had shorter hospital length of stay, but overall longer medication treatment time

Phenobarbital: Use in NAS• Polysubstance exposed neonate

• Commonly used dosing:• Loading dose of 20 mg/kg (given in 1 or 2 doses) • Maintenance dose of 5 mg/kg/day

Clonidine• 2nd line medication• Type of drug: CNS alpha2 receptor agonist

• Pharmacokinetics• Inhibits sympathetic outflow • Reduces catecholamine release

ClonidineADVANTAGES DISADVANTAGES

Reduced LOS when combined with other NAS medications

• Reduced blood pressure & heart rate (reduced catecholamine release)

• Weaned too quickly rebound hypertension & tachycardia

Clonidine: Use in NAS• Used to treat withdrawal in neonates, children,

& adults

• Conflicting data on morphine alone vs. morphine/clonidine combination

• Commonly used dosing: unknown • Reports of every 3, 4, or 6 hours • Reports of continuous drug delivery

BENEFITS OF COMPLIANCE WITH A STANDARDIZED GUIDELINEOhio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence SyndromeWalsh MC, Crowley M, Wexelblatt S, et al. Pediatrics. 2018;141(4): e20170900

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Multi-modal quality improvement initiative

GOAL 1 Standardize identification, nonpharmacologic & pharmacologic treatment in Level 2 & 3 NICUs

GOAL 2 Reduce the use of & length of treatment in same Level 2 & 3 NICUs

GOAL 3 Reduce hospital length of stay in pharmacologically treated newborns with NAS

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

• Ninety-six percent of Ohio NICU’s participated• Nearly half of babies received pharmacologic

treatment

Compliance PRE-intervention

POST-intervention

Nonpharmacologic bundle 37% 59%

Pharmacologic bundle 59% 68%

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Ohio Statewide Collaborative Quality Improvement Project

Nonpharmacologic ALL OR NONE

1: Swaddling

2: Low Stimulation or Rooming In

3: Breast milk and/or Low Lactose

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Ohio Statewide Collaborative Quality Improvement Project

Pharmacologic ALL OR NONE

1: Treatment initiated appropriately

2: Unit primary opiate given

3: Weaning begun 48hr after stabilization

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Pharmacologic Intermediate process

1: Frequency of dose escalation

2: Failed weaning

3: Percent of infants with either or both

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Ohio Statewide Collaborative Quality Improvement Project

Nonpharmacologic bundle compliance

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

• Significant improvements in this bundle

• Centerline shift: increase by 21% from 37% to 59%

Nonpharmacologic bundle compliance

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

• Criteria met in individual elements

• Outcome only reported for Morphine in this bundle

• Centerline shift: Increase from 59% to 68%

*Missing Methadone cohort (i.e. Underreporting true compliance)

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Pharmacologic bundle

compliance

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Pharmacologic bundle compliance• Criteria met in individual elements

• Significant decrease in failed weaning/dose escalation

• Centerline shift: Decrease from 67% to 59%

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Pharmacologic Intermediate

process

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Average length of treatment decreased

from 33.8 to 21.3

days

Ohio Statewide Collaborative Quality Improvement Project

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

Average length of stay

decreased from

18.3 to 17 days

Therefore, high confidence

that

Takeaways

Walsh MC, Crowley M, Wexelblatt S, et al. Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome. Pediatrics. 2018;141(4):e20170900

• High reliability achieved with unit-specific opioid (99%)

• High reliability achieved with weaning protocol (87%)

• Total compliance measure was reduced b the component of treatment initiation (68%), influenced by Finnegan scoring

Promoting a uniform, standardized approachto pharmacologic treatment

is effective in reducing variability & outcomes

INDIVIDUAL HOSPITAL GUIDELINES

• University of Florida/Jacksonville• Winnie Palmer• Baycare

NAS PROTOCOL/GUIDELINES

UF Health/Jacksonville

UF/Jacksonville

NAS Capture protocol

Weaning protocol

SEVERE NAS protocol

Can’t be adequately captured or weaned

Buprenorphine4.5 ug/kg/dose q 8

hours

Initiate buprenorphine when 2 consecutive scores >8 or 1 score >12 despite maximization of non-pharmacologic measures.

CAPTURE protocol

BuprenorphineIncrease by 1.5 ug/kg/dose every

1-2 doses until 2 scores <8

Weaning algorithm

Scores <8Wean Q24 hours

Scores >8

Scores <8Wean Q24 hours

Severe NAS protocol

Achieved max dose (7.5 ug/kg/dose) AND scores >8

• Buprenorphine concentration: 75 ug/ml: compounded with 30% ethanol and simple syrup. If volume greater than 0.5 ml give in 2 separate aliquots with pacifier (2 minutes apart) to help absorption.

• Once captured, consider PT/OT consultation

Buprenorphine4.5 ug/kg/dose q 8

hours

WEANING protocol

Weaning algorithm

Scores <8Wean Q24 hours

NOTES:• Caregiver rooming (if appropriate and room available) has been shown to facilitate timely weaning.• If scores average >8 DO NOT wean. • If scores average <6 consider weaning the dose as early as 16 hours• Go to Severe NAS protocol if patient can’t be weaned every 2-3 days • Once medication is discontinued observed patient for 1-2 days.

BUPRENORPHINEWean to 3 ug/kg Q8 hours for 24 hours

BUPRENORPHINEWean to 1.5 ug/kg Q8 hours for 24 hours

BUPRENORPHINEWean to 1.5 ug/kg Q12 hours for 24 hours

STOP BUPRENORPHINE

SEVERE NAS protocol

• Use for patients who can’t be adequately captured or weaned efficiently. • Ensure all non-pharmacologic measures are maximized (parent/cuddler holding, rooming in)• Notify NAS experts of severe NAS case

CLONIDINE2 ug/kg/dose q 6 hours

Wean BUPRENORPHINE• “Normal” buprenorphine dose (<3

ug/kg/dose): Using Weaning protocol until buprenorphine discontinued

• “High” buprenorphine dose (>3ug/kg/dose): Wean buprenorphine dose by 25% every 24 hours until at 3 ug/kg/dose use weaning protocol until buprenorphine discontinued

Scores <8

Wean CLONIDINEto 1 ug/kg/dose q 6 hours for 24

hours

Once buprenorphine discontinued

Wean CLONIDINEto 1 ug/kg/dose q 6 hours for 12

hours

Acceptable scores, blood pressure, &

heart rate

Acceptable scores, blood pressure, &

heart rate

Stop CLONIDINE

Notes with Severe NAS protocol• Clonidine

• Measure blood pressure Q6 hours while on clonidine & for 1-2 days after clonidine is discontinued.

• Hold clonidine dose if mean blood pressure < 40 mmHg and/or heart rate <100 bpm.

• If patient doesn’t respond to buprenorphine & clonidine use Phenobarbital

• Load with Phenobarbital (10 mg/kg) x2 doses 12 hours apart• Start maintenance dose of 2.5 mg/kg twice a day• Once average scores are <8 wean buprenorphine 1st, clonidine

2nd , & phenobarbital 3rd

• Once off all medications, the severe NAS patient should be monitored for 2 days for rebound NAS signs.

NAS PROTOCOL/GUIDELINES

Winnie Palmer

Winnie Palmer Hospital NICU Protocol for NAS therapy

Winnie Palmer Hospital NICU Protocol for NAS therapy

Morphine – initiationBegin morphine with 2 scores > 8, 1 hour apart• 9-12 = 0.04 mg every 3-4 hours• 13-16 = 0.08 mg every 3-4 hours• 17-20 = 0.12 mg every 3-4 hours• 21-24 = 0.16 mg every 3-4 hours• > 25 = 0.20 mg every 3-4 hours

Winnie Palmer Hospital NICU Protocol for NAS therapy

Morphine – continuation therapy• For each subsequent score > 8, increase dose by:

• 9-12 = 0.02 mg every 3-4 hours• 13-16 = 0.04 mg every 3-4 hours• 17-20 = 0.06 mg every 3-4 hours• 21-24 = 0.08 mg every 3-4 hours• > 25 = 0.1 mg every 3-4 hours

• Subsequent dosing every 3-4 hours

• If morphine reaches 0.1 mg/kg every 3-4 hours and scores are still > 8, add Clonidine at 1 mcg/kg every 6 hours. May increase to 2-3 mcg/kg q 6 hr

Winnie Palmer Hospital NICU Protocol for NAS therapy

Morphine – weaning• Once scores are <8 for 48 hours, may begin

to wean morphine by 0.02 mg every 24• May decrease more rapidly with scores <5

• Once off morphine for 24 hours with scores <8, reduce Clonidine dose b 50% for 24 hours, then discontinue Clonidine

Winnie Palmer Hospital NICU Protocol for NAS therapy

Morphine – re-escalation• If scores increase to > 8 on 2 occasions after

weaning was started, increase dose with each score >8 by:• 9-12 = 0.01 mg every 3-4 hours• 13-16 = 0.02 mg every 3-4 hours• 17-20 = 0.03 mg every 3-4 hours• 21-24 = 0.04 mg every 3-4 hours• > 25 = 0.05 mg every 3-4 hours

Winnie Palmer Hospital NICU Protocol for NAS therapy

Clonidine – weaning• If clonidine was given, continue at the

maximum dose until morphine has been stopped for 24 hours.

• Wean by 50% and watch for tachycardia or hypertension or increased NAS scores

• If stable for 24 hours, discontinue clonidine and observe for another 24-48 hours.

Winnie Palmer Hospital NICU Protocol for NAS therapy

NAS PROTOCOL/GUIDELINES

BaycareSt Joseph’s Women’s Hospital

Early medication protocol: Morphine

• Scores DURING FIRST 1-2 days of withdrawal

• >8 intermittently or 1 scores >12 start Morphine dose 0.04 mg/kg/dose q3 hours

• Consistent scores >12 start Morphine at 0.06 mg/kg/dose q3 hours

• Scores DURING FIRST 1-2 days of treatment for withdrawal

• Continues with high NAS scores (2 scores of 9-12 or 1 score >12)increase Morphine dose by 0.01-0.02 mg/kg/dose q 3h

**MAX Morphine dose used 0.08mg/kg/dose q3h**

• Must assess the effect for 12 hours before another increase

Medication escalation: Morphine

• Add Clonidine when • Morphine at 0.08 mg/kg/dose• IF 2 scores 9-12 or 1 score >12

• Start Clonidine at 1 mcg/kg/dose q3h

• Must assess the effect for 12 hours before another increase.

• Clonidine monitoring: blood pressure & heart rate before dose administered

• Hold Clonidine dose if heart rate <100 bpm or systolic blood pressure <60 mmHg

Medication escalation: Adding Clonidine

• Increase Clonidine dose IF 2 scores 9-12 or 1 score >12

• Can increase Clonidine • 1st increase to 2 mcg/kg/dose q3 hours• 2nd increase to 2.5 mcg/kg/dose q3 hours• 3rd increase to 3 mcg/kg/dose q3 hours

• Must assess the effect for 12 hours before another increase

• Clonidine monitoring: blood pressure & heart rate before dose administered

• Hold Clonidine dose if heart rate <100 bpm or systolic blood pressure <60 mmHg

Medication escalation: Clonidine

When Morphine at 0.08 mg/kg/dose & Clonidine at 3 mcg/kg/dose

IF Morphine preferred• Increase Morphine to 0.09 mg/kg/dose q3 hours, then to 0.1

mg/kg/dose, then to 0.11 mg/kg, then to 0.12 mg/kg/doseTHIS DOSE MAY LEAD TO IATROGENIC CONCERNS

• Must assess the effect for 12 hours before EACH increase

IF Clonidine preferred• Increase Clonidine doses 3.5mcg/kg/dose, then 4mcg/kg/dose

Medication escalation: High doses of Morphine & Clonidine

ALWAYS wean morphine BEFORE Clonidine (regardless of Morphine dose)

• Decrease Morphine by ~10% for every 18-30 hours that scores AVERAGE <8

• When Morphine is at 0.09 mg/kg/dose q3 hours, go to 0.08 mg/kg/dose q3 hours, then to 0.07 mg/kg/dose, 0.06 mg/kg/dose, 0.05 mg/kg/dose...

• If scores are higher after weaning, assess the effect for 12 hours before returning to the previous dose

Medication weaning: Morphine

ALWAYS wean morphine BEFORE Clonidine (regardless of Morphine dose)

• Once Morphine is at 0.04-0.05 mg/kg/dose Q3 hours, frequency can be spaced (still before Clonidine weaning)

• Decrease Morphine frequency to q6 hours for 18-30 hours• IF scores AVERAGE ≤8 can continue weaning

frequency (e.g., if at 0.05 mg/kg/dose q3 hours wean to q6 hours, then q12 hours, then discontinue)

• If scores are higher after weaning, assess the effect for 12 hours before returning to the previous interval

Medication weaning: Morphine

• Once Morphine has been discontinued for 18-30 hours, consider Clonidine weaning

• Decrease Clonidine dose by 1 mcg/kg/dose changes

• Decrease Clonidine frequency once at 1 mcg/kg/dose• Start at q6 hour frequency for 18-30 hours• IF scores AVERAGE ≤8 can continue weaning

frequency (e.g., if at q6 hours wean to q12 hours, then discontinue)

• If scores are higher after weaning, assess the effect for 12 hours before returning to the previous interval

Medication weaning: Clonidine

USING PROCESS MAPPING IN NAS

Maya Balakrishnan & Karen Fugate

What is a process flow map?

• Tool in your toolbox• Easy-to-understand

visual model of a process

• Standardizes a process• Can improve efficiency• Sequence of steps to

get from “A” “B”

AKA, Flowcharts, Flow maps, Flow diagrams, Algorithms

Why use a process flow map for NAS

management?

• Clarify current state • Basis for discussion• Standardize a process

• Communicate a process • Clarify process for team &

others

• Analyze a process• Opportunities, inefficiencies,

bottlenecks

Process map symbols

• Start/End

• Step

• Decision

• Delay

• Direction

Current state map

NOTE: Vagueness allows for subjectivity How can we ensure reliability &

consistency?

• Clarifies current state• Communicates the process• Analyze the process

Future state map• Keep it simple & readable

Future state map• There ONE start point & ONE

stop point

Future state map• Every decision point (i.e.,

question) has only ONE response– ONE yes or ONE no

Future state map• The process needs to always

lead back to main algorithm if veers off (i.e., if there is a decision point yes or no response)

Tips on mapping

• “Walk” or observe the outlined process

• Sketch your map (sticky notes, butcher paper) use an online application to create a Process map

Microsoft Word™, Excel™• https://www.wikihow.com/Create-a-Process-Flowchart

Lucidchart.com (Free trial software)• https://www.lucidchart.com/

Our challenge to your team

Develop a pharmacologic treatment algorithm forNAS & share it with our FPQC teams

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Save the Date: April 4-5, TampaFPQC 2019 Conference

Racial/ethnic disparities in maternal mortality & morbidity – Elizabeth Howell, MD, MPPProfessor of Population Health Sciences & Policy, Obstetrics, Gynecology, and Reproductive Science, & Psychiatry, Mount Sinai Health System

Parent topic – LelisVernonNICU Mom, National Network of Perinatal Quality Collaboratives, Patient and Family Centered Care advocate

Racial/ethnic disparities in NICU care quality – JochenProfit, MD

Associate Professor of Pediatrics (Neonatology), Stanford University

Change Management– Bethany Robertson, DNP, CNMAssistant Professor Clinical, Emory University

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Tuesday, February 19 at 1:00 pm ET

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